Arg120Gly mutations in CryAB (CryABR120G) can cause desmin-related cardiomyopathy (DRM), which is characterized by accumulation of aggregated desmin and CryAB in the sarcoplasm of cardiomyocytes, leading to cardiomyopathy and premature death in transgenic (TG) mouse models. Our lab has identified the intracellular inclusion bodies formed by CryABR120G mutations as aggresomes, which have similar morphological features to the protein aggregates observed in many neurodegenerative diseases. Indeed, CryABR120G TG mice contain amyloid-like proteins that are positively stained with an antibody targeting the conformation of a cytotoxic pre-amyloid oligomer (PAO), suggesting that DRM is a cardiac protein conformation disease which may be prevalent in many forms of human heart failure. Data suggests that the aggregation phenotype is caused, in part, by functional defects in the normal mechanisms of degrading misfolded proteins. The goal of the proposed research is to test the hypothesis that restoring functional deficits in protein degradation pathways can be protective in CryABR120G-based cardiomyopathy, leading to a reduction in aggregate formation and improved heart function. We have proposed two specific aims to test how modulating components of protein degradation routes can affect aberrant protein aggregation in CryABR120G-based DRM: 1) PAO removal/degradation by neprilysin, a protein shown to degrade soluble oligomers in similar diseases, will impact favorably on CryABR120G pathogenesis and 2) By decreasing protein traffic towards impaired degradation compartments (achieved by reducing the level of the cochaperone/E3 ubiquitin ligase CHIP), we can maintain or even restore the degradation capacity of these compartments by reducing the influx of misfolded protein, which will reduce protein accumulation and toxicity. The proposed studies will determine if protein aggregation in CryABR120G is caused by deficits in protein degradation machinery in the heart and, more importantly, determine if genetic modulation of these pathways can be protective in our model. Understanding the role played by malfunctioning degradation in protein conformation diseases could lead to targeted therapeutics to prevent or delay the onset of toxic protein aggregates, and may be widely applicable to a host of similar disease phenotypes in the heart and other tissues.